tbuckley/cabot-search huggingface dataset:
XGBoost framework with feature selection for the prediction of RNA N5-methylcytosine sites
Authors: Zeeshan Abbas, Mobeen ur Rehman, Hilal Tayara, Quan Zou, Kil To Chong
Journal: Molecular Therapy (2023)

5-methylcytosine (m5C) is indeed a critical post-transcriptional alteration that is widely present in various kinds of RNAs and is crucial to the fundamental biological processes. By correctly identifying the m5C-methylation sites on RNA, clinicians can more clearly comprehend the precise function of these m5C-sites in different biological processes. Due to their effectiveness and affordability, computational methods have received greater attention over the last few years for the identification of methylation sites in various species. To precisely identify RNA m5C locations in five different species including Homo sapiens, Arabidopsis thaliana, Mus musculus, Drosophila melanogaster, and Danio rerio, we proposed a more effective and accurate model named m5C-pred. To create m5C-pred, five distinct feature encoding techniques were combined to extract features from the RNA sequence, and then we used SHapley Additive exPlanations to choose the best features among them, followed by XGBoost as a classifier. We applied the novel optimization method called Optuna to quickly and efficiently determine the best hyperparameters. Finally, the proposed model was evaluated using independent test datasets, and we compared the results with the previous methods. Our approach, m5C- pred, is anticipated to be useful for accurately identifying m5C sites, outperforming the currently available state-of-the-art techniques. 5-methylcytosine (m5C) is indeed a critical post-transcriptional alteration that is widely present in various kinds of RNAs and is crucial to the fundamental biological processes. By correctly identifying the m5C-methylation sites on RNA, clinicians can more clearly comprehend the precise function of these m5C-sites in different biological processes. Due to their effectiveness and affordability, computational methods have received greater attention over the last few years for the identification of methylation sites in various species. To precisely identify RNA m5C locations in five different species including Homo sapiens, Arabidopsis thaliana, Mus musculus, Drosophila melanogaster, and Danio rerio, we proposed a more effective and accurate model named m5C-pred. To create m5C-pred, five distinct feature encoding techniques were combined to extract features from the RNA sequence, and then we used SHapley Additive exPlanations to choose the best features among them, followed by XGBoost as a classifier. We applied the novel optimization method called Optuna to quickly and efficiently determine the best hyperparameters. Finally, the proposed model was evaluated using independent test datasets, and we compared the results with the previous methods. Our approach, m5C- pred, is anticipated to be useful for accurately identifying m5C sites, outperforming the currently available state-of-the-art techniques.
Abstract B018: Loss of androgen receptor-mediated repression leads to EphA2 overexpression that promotes cellular dedifferentiation and castration resistance of prostate cancer through noncanonical signaling
Authors: Ryan Lingerak, Bingcheng Wang
Journal: Cancer Research (2023)

Abstract As a member of Eph subfamily receptor tyrosine kinases, EphA2 has been extensively studied in cancer. It is frequently overexpressed in many different types of human cancer, which is often correlated with tumor progression. We reported recently that EphA2 has diametrically opposite roles in regulating PCa cell differentiation, proliferation, migration, and invasion. In the presence of ligands called ephrin-As, EphA2 canonical signaling inhibits Ras/ERK and PI3K/Akt pathways and suppressed cell proliferation and migration. In contrast, in the absence of ligands EphA2 mediates noncanonical signaling, which promotes chemotactic migration and invasion and accentuates the tumor cell stem properties. Interestingly the ligand-independent noncanonical signaling is correlated with phosphorylation of EphA2 on serine 897 (S897). S897A mutation abolished this ligand-independent effect on cell differentiation and migration and suppressed tumor development in PC3 xenograft model. In mouse prostate, EphA2 is expressed in the stem cell niche together with its cognate ephrin-A ligands in the peri-urethra region but is repressed in AR-positive, differentiated prostate epithelial cells. During progression toward CRPC, ephrin-ligand expression is reduced while EphA2 is overexpressed, facilitating ligand-independent noncanonical signaling by EphA2. Consistent with the negative roles of AR in regulating EphA2 expression, treatment with anti-AR enzalutamide promotes EphA2 expression. In contrast, activating AR with DHT strongly suppressed EphA2 expression. Knockout of EphA2 in the AR+ LAPC4 cells, delayed progression towards castration resistance in vivo. Our results unveiled the previously unknown functional crosstalk between AR and EphA2, and the important role of EphA2 in the malignant progression of prostate cancer. Citation Format: Ryan Lingerak, Bingcheng Wang. Loss of androgen receptor-mediated repression leads to EphA2 overexpression that promotes cellular dedifferentiation and castration resistance of prostate cancer through noncanonical signaling [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B018.
Abstract B003: EVI1 oncogenic role in non-canonical AR driven lethal prostate cancer
Authors: Surendra Gulla, Jonathan E. Bard, David J. VanderWeele, Kathleen Kelly, Remi Adelaiye-Ogala
Journal: Cancer Research (2023)

Abstract Androgen receptor (AR) remains active in castration-resistant prostate cancer (CRPC), and AR cistrome can become extensively reprogrammed with disease progression. Recent findings from our group and others have shown an association with non-canonical AR signature with resistance to enzalutamide. However, the complete mechanism is not fully revealed. EVI1 belongs to the zinc-finger transcription factor family, and overexpression of EVI1 is associated with poor patient outcomes. However, its role in the context of resistance to AR-targeted therapy remains unclear. Our preliminary data from ChIP-seq and GSEA analysis shows a significant enrichment of EVI1 target gene-set captured from annotated enzalutamide-resistant AR binding sites. Hypothesis: EVI1 cooperates in regulating the non-canonical AR activity associated with resistance to AR targeted therapy and blocking EVI1 may overcome resistance to target therapy. Methods : Using a PDX model of advanced enzalutamide-resistant CRPC, we performed single-cell ATAC-seq + gene expression multi-omic assay. Next, we determined the enrichment of canonical vs. non-canonical AR signatures across cell populations. Using motif analysis and transcription factor foot printing, we determine EVI1 (MECOM) motif z score and enrichment. Results: Our findings demonstrate enrichment of non-canonical AR signatures in distinct population of cells following exposure to enzalutamide. In addition, the subpopulation of cells enriched for non-canonical AR cistrome also exhibited high EVI1 (MECOM) motif z-scores. Conclusion : Our data suggests a potential link between EVI1 and non-canonical AR signaling. Ongoing mechanistic studies will provide insight mechanism by which EVI1 controls non canonical AR activity and its vulnerabilities. Citation Format: Surendra Gulla, Jonathan E. Bard, David J. VanderWeele, Kathleen Kelly, Remi Adelaiye-Ogala. EVI1 oncogenic role in non-canonical AR driven lethal prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B003.
Secreted Akkermansia muciniphila threonyl-tRNA synthetase functions to monitor and modulate immune homeostasis
Authors: Su-Man Kim, Shinhye Park, Seung-Ho Hwang, Eun-Young Lee, Jong-Hwan Kim, Ga Seul Lee, Giljae Lee, Dong-Ho Chang, Jae-Geun Lee, Jungwon Hwang, Youngjin Lee, Minsoo Kyung, Eun-Kyoung Kim, Jae-Hoon Kim, Tae-Hwan Kim, Jeong Hee Moon, Byoung-Chan Kim, GwangPyo Ko, Seon-Young Kim, Ji-Hwan Ryu, Jeong-Soo Lee, Chul-Ho Lee, Jeong-Yoon Kim, Sunghoon Kim, Won-Jae Lee, Myung Hee Kim
Journal: Cell Host & Microbe (2023)

Commensal bacteria are critically involved in the establishment of tolerance against inflammatory challenges, the molecular mechanisms of which are just being uncovered. All kingdoms of life produce aminoacyl-tRNA synthetases (ARSs). Thus far, the non-translational roles of ARSs have largely been reported in eukaryotes. Here, we report that the threonyl-tRNA synthetase (AmTARS) of the gut-associated bacterium Akkermansia muciniphila is secreted and functions to monitor and modulate immune homeostasis. Secreted AmTARS triggers M2 macrophage polarization and orchestrates the production of anti-inflammatory IL-10 via its unique, evolutionary-acquired regions, which mediates specific interactions with TLR2. This interaction activates the MAPK and PI3K/AKT signaling pathways, which converge on CREB, leading to an efficient production of IL-10 and suppression of the central inflammatory mediator NF-κB. AmTARS restores IL-10-positive macrophages, increases IL-10 levels in the serum, and attenuates the pathological effects in colitis mice. Thus, commensal tRNA synthetases can act as intrinsic mediators that maintain homeostasis.
Targeted deprivation of methionine with engineered Salmonella leads to oncolysis and suppression of metastasis in broad types of animal tumor models
Authors: Sujin Zhou, Yan Lin, Zhenggang Zhao, Yunhao Lai, Mengmeng Lu, Zishen Shao, Xinyu Mo, Yunping Mu, Zhipeng Liang, Xinxing Wang, Jingming Qu, Hua Shen, Fanghong Li, Allan Z. Zhao
Journal: Cell Reports Medicine (2023)

The strong dependency of almost all malignant tumors on methionine potentially offers a pathway for cancer treatment. We engineer an attenuated strain of Salmonella typhimurium to overexpress an L-methioninase with the aim of specifically depriving tumor tissues of methionine. The engineered microbes target solid tumors and induce a sharp regression in several very divergent animal models of human carcinomas, cause a significant decrease in tumor cell invasion, and essentially eliminate the growth and metastasis of these tumors. RNA sequencing analyses reveal that the engineered Salmonella reduce the expression of a series of genes promoting cell growth, cell migration, and invasion. These findings point to a potential treatment modality for many metastatic solid tumors, which warrants further tests in clinical trials.
Shining a Light on Cancer—Photonics in Microfluidic Tumor Modeling and Biosensing (Adv. Healthcare Mater. 14/2023)
Authors: Carlos F. Guimarães, Daniela Cruz‐Moreira, David Caballero, Rogério P. Pirraco, Luca Gasperini, Subhas C. Kundu, Rui L. Reis
Journal: Advanced Healthcare Materials (2023)

Biofabrication In article 2201442, Subhas C. Kundu, Rui L. Reis, and co-workers explore the current landscape and potential future impact of photonics in microfluidic cancer modelling and biosensing. The manipulation of light within these miniaturized systems exposes unique opportunities where lightning-fast interactions can both enable the fabrication of physiologically-relevant 3D biological architectures and quantification of complex biological processes with unprecedented throughput towards data-driven cancer research.
Association of Virulent <i>Helicobacter pylori</i> Strains With Ischemic Heart Disease
Authors: Vincenzo Pasceri, Giovanni Cammarota, Giuseppe Patti, Lucio Cuoco, Antonio Gasbarrini, Rita L. Grillo, Giuseppe Fedeli, Giovanni Gasbarrini, Attilio Maseri
Journal: Circulation (1998)

Background —Previous studies have reported an association between chronic Helicobacter pylori infection and ischemic heart disease. However, it is not clear whether this association is really due to the virulence of the bacterium or is merely the result of confounding factors (in particular, age and social class). Methods and Results —We assessed the prevalence of infection by Helicobacter pylori and by strains bearing the cytotoxin-associated gene-A (CagA), a strong virulence factor, in 88 patients with ischemic heart disease (age, 57±8 years; 74 men) and in 88 age- and sex-matched controls (age, 57±8 years; 74 men) with similar social background. Prevalence of Helicobacter infection was significantly higher in patients than in controls (62% versus 40%; P =.004), with an odds ratio of 2.8 (95% CI, 1.3 to 7.4; P &lt;.001) adjusted for age, sex, main cardiovascular risk factors, and social class. Patients with ischemic heart disease also had a higher prevalence of CagA-positive strains (43% versus 17%; P =.0002), with an adjusted odds ratio of 3.8 (95% CI, 1.6 to 9.1; P &lt;.001). Conversely, prevalence of CagA-negative strains was similar in patients and controls (19% versus 23%), with an adjusted odds ratio of 0.8 (95% CI, 0.4 to 1.4). Conclusions —The association between Helicobacter pylori and ischemic heart disease seems to be due to a higher prevalence of more virulent Helicobacter strains in patients. These results support the hypothesis that Helicobacter pylori may influence atherogenesis through low-grade, persistent inflammatory stimulation.
The MDM2–p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced or Metastatic Solid Tumors: Results of a Phase Ia, First-in-Human, Dose-Escalation Study
Authors: Patricia LoRusso, Noboru Yamamoto, Manish R. Patel, Scott A. Laurie, Todd M. Bauer, Junxian Geng, Teffany Davenport, Michael Teufel, Jian Li, Mehdi Lahmar, Mrinal M. Gounder
Journal: Cancer Discovery (2023)

Abstract Brigimadlin (BI 907828) is an oral MDM2–p53 antagonist that has shown encouraging antitumor activity in vivo. We present phase Ia results from an open-label, first-in-human, phase Ia/Ib study investigating brigimadlin in patients with advanced solid tumors (NCT03449381). Fifty-four patients received escalating doses of brigimadlin on day 1 of 21-day cycles (D1q3w) or days 1 and 8 of 28-day cycles (D1D8q4w). Based on dose-limiting toxicities during cycle 1, the maximum tolerated dose was selected as 60 mg for D1q3w and 45 mg for D1D8q4w. The most common treatment-related adverse events (TRAE) were nausea (74.1%) and vomiting (51.9%); the most common grade ≥3 TRAEs were thrombocytopenia (25.9%) and neutropenia (24.1%). As evidence of target engagement, time- and dose-dependent increases in growth differentiation factor 15 levels were seen. Preliminary efficacy was encouraging (11.1% overall response and 74.1% disease control rates), particularly in patients with well-differentiated or dedifferentiated liposarcoma (100% and 75% disease control rates, respectively). Significance: We report phase Ia data indicating that the oral MDM2–p53 antagonist brigimadlin has a manageable safety profile and shows encouraging signs of efficacy in patients with solid tumors, particularly those with MDM2-amplified advanced/metastatic well-differentiated or dedifferentiated liposarcoma. Further clinical investigation of brigimadlin is ongoing. See related commentary by Italiano, p. 1765. This article is highlighted in the In This Issue feature, p. 1749
Long-term Risks of Recurrence After Hospital Discharge for Acute Lower Gastrointestinal Bleeding: A Large Nationwide Cohort Study
Authors: Yoshinori Sato, Tomonori Aoki, Eiji Sadashima, Yusuke Nakamoto, Katsumasa Kobayashi, Atsushi Yamauchi, Atsuo Yamada, Jun Omori, Takashi Ikeya, Taiki Aoyama, Naoyuki Tominaga, Takaaki Kishino, Naoki Ishii, Tsunaki Sawada, Masaki Murata, Akinari Takao, Kazuhiro Mizukami, Ken Kinjo, Shunji Fujimori, Takahiro Uotani, Minoru Fujita, Hiroki Sato, Sho Suzuki, Toshiaki Narasaka, Junnosuke Hayasaka, Tomohiro Funabiki, Yuzuru Kinjo, Akira Mizuki, Shu Kiyotoki, Tatsuya Mikami, Ryosuke Gushima, Hiroyuki Fujii, Yuta Fuyuno, Naohiko Gunji, Yosuke Toya, Kazuyuki Narimatsu, Noriaki Manabe, Koji Nagaike, Tetsu Kinjo, Yorinobu Sumida, Sadahiro Funakoshi, Kiyonori Kobayashi, Tamotsu Matsuhashi, Yuga Komaki, Tadateru Maehata, Keisuke Tateishi, Mitsuru Kaise, Naoyoshi Nagata
Journal: Clinical Gastroenterology and Hepatology (2023)

Currently, large, nationwide, long-term follow-up data on acute lower gastrointestinal bleeding (ALGIB) are scarce. We investigated long-term risks of recurrence after hospital discharge for ALGIB using a large multicenter dataset.
CXCR2 expression during melanoma tumorigenesis controls transcriptional programs that facilitate tumor growth
Authors: J. Yang, K. Bergdorf, C. Yan, W. Luo, S. C. Chen, G.D. Ayers, Q. Liu, X. Liu, M. Boothby, V.L. Weiss, S. M. Groves, A. N. Oleskie, X. Zhang, D. Y. Maeda, J. A. Zebala, V. Quaranta, A. Richmond
Journal: Molecular Cancer (2023)

Abstract Background Though the CXCR2 chemokine receptor is known to play a key role in cancer growth and response to therapy, a direct link between expression of CXCR2 in tumor progenitor cells during induction of tumorigenesis has not been established. Methods To characterize the role of CXCR2 during melanoma tumorigenesis, we generated tamoxifen-inducible tyrosinase-promoter driven Braf V600E /Pten −/− /Cxcr2 −/− and NRas Q61R /INK4a −/− /Cxcr2 −/− melanoma models. In addition, the effects of a CXCR1/CXCR2 antagonist, SX-682, on melanoma tumorigenesis were evaluated in Braf V600E /Pten −/− and NRas Q61R /INK4a −/− mice and in melanoma cell lines. Potential mechanisms by which Cxcr2 affects melanoma tumorigenesis in these murine models were explored using RNAseq, mMCP-counter, ChIPseq, and qRT-PCR; flow cytometry, and reverse phosphoprotein analysis (RPPA). Results Genetic loss of Cxcr2 or pharmacological inhibition of CXCR1/CXCR2 during melanoma tumor induction resulted in key changes in gene expression that reduced tumor incidence/growth and increased anti-tumor immunity. Interestingly, after Cxcr2 ablation, Tfcp2l1 , a key tumor suppressive transcription factor, was the only gene significantly induced with a log 2 fold-change greater than 2 in these three different melanoma models . Conclusions Here, we provide novel mechanistic insight revealing how loss of Cxcr2 expression/activity in melanoma tumor progenitor cells results in reduced tumor burden and creation of an anti-tumor immune microenvironment. This mechanism entails an increase in expression of the tumor suppressive transcription factor, Tfcp2l1, along with alteration in the expression of genes involved in growth regulation, tumor suppression, stemness, differentiation, and immune modulation. These gene expression changes are coincident with reduction in the activation of key growth regulatory pathways, including AKT and mTOR.
Management of immune-related cutaneous adverse events with dupilumab
Authors: Alyce Mei-Shiuan Kuo, Stephanie Gu, Joseph Stoll, Andrea P Moy, Stephen W Dusza, Allison Gordon, Elena C Haliasos, Yelena Janjigian, Lukas Kraehenbuehl, Elizabeth A Quigley, Paul Chapman, Mario E Lacouture, Alina Markova
Journal: Journal for ImmunoTherapy of Cancer (2023)

Immune checkpoint inhibitors (ICI) target the PD-1/PD-L1 and CTLA-4 pathways and allows the immune system to deliver antitumor effects. However, it is also associated with well-documented immune-related cutaneous adverse events (ircAEs), affecting up to 70–90% of patients on ICI. In this study, we describe the characteristics of and patient outcomes with ICI-associated steroid-refractory or steroid-dependent ircAEs treated with dupilumab. Patients with ircAEs treated with dupilumab between March 28, 2017, and October 1, 2021, at Memorial Sloan Kettering Cancer Center were included in this retrospective study, which assessed the rate of clinical response of the ircAE to dupilumab and any associated adverse events (AEs). Laboratory values were compared before and after dupilumab. All available biopsies of the ircAEs were reviewed by a dermatopathologist. Thirty-four of 39 patients (87%, 95% CI: 73% to 96%) responded to dupilumab. Among these 34 responders, 15 (44.1%) were complete responders with total ircAE resolution and 19 (55.9%) were partial responders with significant clinical improvement or reduction in severity. Only 1 patient (2.6%) discontinued therapy due to AEs, specifically, injection site reaction. Average eosinophil counts decreased by 0.2 K/mcL (p=0.0086). Relative eosinophils decreased by a mean of 2.6% (p=0.0152). Total serum immunoglobulin E levels decreased by an average of 372.1 kU/L (p=0.0728). The most common primary inflammatory patterns identified on histopathological examination were spongiotic dermatitis (n=13, 33.3%) and interface dermatitis (n=5, 12.8%). Dupilumab is a promising option for steroid-refractory or steroid-dependent immune-related cutaneous adverse events, particularly those that are eczematous, maculopapular, or pruritic. Among this cohort, dupilumab was well-tolerated with a high overall response rate. Nonetheless, prospective, randomized, controlled trials are warranted to confirm these observations and confirm its long-term safety.
Gelatinous larvacean zooplankton can enhance trophic transfer and carbon sequestration
Authors: Cornelia Jaspers, Russell R. Hopcroft, Thomas Kiørboe, Fabien Lombard, Ángel López-Urrutia, Jason D. Everett, Anthony J. Richardson
Journal: Trends in Ecology & Evolution (2023)

Larvaceans are gelatinous zooplankton abundant throughout the ocean. Larvaceans have been overlooked in research because they are difficult to collect and are perceived as being unimportant in biogeochemical cycles and food-webs. We synthesise evidence that their unique biology enables larvaceans to transfer more carbon to higher trophic levels and deeper into the ocean than is commonly appreciated. Larvaceans could become even more important in the Anthropocene because they eat small phytoplankton that are predicted to become more prevalent under climate change, thus moderating projected future declines in ocean productivity and fisheries. We identify critical knowledge gaps and argue that larvaceans should be incorporated into ecosystem assessments and biogeochemical models to improve predictions of the future ocean.